He, Wei, Verhees, Gerrik F., Bhagwat, Nikhil, Yang, Ye, Kulkarni, Dhananjaya S., Lombardo, Zane, Lahiri, Sudipta, Roy, Pritha, Zhuo, Jiaming, Dang, Brian, Snyder, Andriana, Shastry, Shashank, Moezpoor, Michael, Alocozy, Lilly, Lee, Kathy Gyehyun, Painter, Daniel, Mukerji, Ishita, and Hunter, Neil
Crossing over is essential for chromosome segregation during meiosis. Protein modification by SUMO is implicated in crossover control, but pertinent targets have remained elusive. Here we identify Msh4 as a target of SUMO-mediated crossover regulation. Msh4 and Msh5 constitute the MutSγ complex, which stabilizes joint-molecule (JM) recombination intermediates and facilitates their resolution into crossovers. Msh4 SUMOylation enhances these processes to ensure that each chromosome pair acquires at least one crossover. Msh4 is directly targeted by E2 conjugase Ubc9, initially becoming mono-SUMOylated in response to DNA double-strand breaks, then multi/poly-SUMOylated forms arise as homologs fully engage. Mechanistically, SUMOylation fosters interaction between Msh4 and Msh5. We infer that initial SUMOylation of Msh4 enhances assembly of MutSγ in anticipation of JM formation, while secondary SUMOylation may promote downstream functions. Regulation of Msh4 by SUMO is distinct and independent of its previously described stabilization by phosphorylation, defining MutSγ as a hub for crossover control. [Display omitted] • Crossover factor Msh4 is a direct target of the SUMO E2-conjugase Ubc9 • Msh4 SUMOylation facilitates meiotic crossing over • SUMOylation fosters interaction between Msh4 and Msh5 • Msh4 SUMOylation is triggered by DNA double-strand breaks Meiotic crossovers promote accurate chromosome segregation. He et al. show that SUMO modifies the recombination factor Msh4, enhancing its interaction with Msh5 to assemble the MutSγ complex, which promotes crossovers. Msh4 SUMOylation requires DNA double-strand breaks, defining a pathway that couples the initiation of recombination to crossover control. [ABSTRACT FROM AUTHOR]